R93W mutation in Orai1 causes impaired calcium influx in platelets.
The intracellular Ca(2+) concentration of many nonexcitable cells is regulated by calcium store release and store-operated calcium entry (SOCE). In platelets, STIM1 was recently identified as the main calcium sensor expressed in the endoplasmic reticulum. To evaluate the role of the SOC channel moiety, Orai1, in platelet SOCE, we generated mice expressing a mutated, inactive form of Orai1 in blood cells only (Orai1(R93W)). Platelets expressing Orai1(R93W) were characterized by markedly reduced SOCE and impaired agonist-induced increases in [Ca(2+)](i). Orai1(R93W) platelets showed reduced integrin activation and impaired degranulation when stimulated with low agonist concentrations under static conditions. This defect, however, did not significantly affect the ability of Orai1(R93W) platelets to aggregate or to adhere to collagen under arterial flow conditions ex vivo. In contrast, these adherent Orai1(R93W) platelets were defective in surface phosphatidylserine exposure, suggesting that Orai1 is crucial for the platelets' procoagulant response rather than for other Ca(2+)-dependent cellular responses.
Bergmeier
Wolfgang
W
Immune Disease Institute and Harvard Medical School, Boston, MA, USA. wolfgang.bergmeier@jefferson.edu
Oh-Hora
Masatsugu
M
McCarl
Christie-Ann
CA
Roden
R Claire
RC
Bray
Paul F
PF
Feske
Stefan
S
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics*; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D051379:Mice; D009154:Mutation; D000071740:ORAI1 Protein; D018183:Transplantation Chimera
D015220:Calcium Channels; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; D002118:Calcium